Despite recent advances in the prevention and treatment of cardiovascular disease, the prevalence of heart failure, a worldwide health threat, continues to grow. Current therapeutic strategies for heart failure are largely directed at disturbances in the neurohormonal axis rather than targeting the myocyte. Evidence is emerging that alterations in myocyte energy metabolism contributes to the pathogenesis of heart failure. Previous work linked to this RO1-funded project has shown that a gene regulatory cascade, under the influence of the transcriptional coactivators, PPAR3 transcriptional coactivator-11 and 2 (PGC-11 and PGC-12), controls the expression of genes involved in a wide array of mitochondrial energy transduction and ATP-generating processes in the cardiac myocyte. The results of our recent studies conducted in mice deficient for the PGC-1 coactivators have shown that the PGC-1 regulatory cascade is required for postnatal mitochondrial biogenic maturation. We have also found that the expression and activity of the PGC-1 coactivators are downregulated in pathologic forms of cardiac hypertrophy and in the failing heart. These findings have led to the central hypothesis of this renewal proposal that chronic deactivation of PGC-1 signaling in the adult heart contributes to the progressive pathologic metabolic and functional remodeling that leads to end-stage heart failure. To test this hypothesis we will: (1) conduct mitochondrial functional and proteomic studies in the hearts of adult mice in which the cardiac PGC-1 gene regulatory cascade has been deactivated; (2) define mitochondrial functional and proteomic derangements in hearts of wild-type mice subjected to pressure overload and ischemic insult and compare the results with the dataset generated in the PGC-1-deficient hearts in order to identify shared signatures; (3) explore the potential role of PGC-1 coactivators in the control of mitochondrial dynamics (fusion, fission, biogenesis); and (4) devise and implement proof-of-concept rescue studies in which PGC-1 coactivators or relevant downstream targets are reactivated in heart failure models in wild-type mice. In the long-term, we seek to identify and validate novel targets aimed at modulating cardiac metabolism as a novel approach to prevent or treat heart failure in its early stages. )